1. Hormone Metabolism BELLA MARILOU BAXA-DAGUPLO, MD Department of Biochemistry & Nutrition Fatima College of Medicine Our Lady of Fatima University (Review ’09)

7. Regulation of Hormone Secretion A. Feedback Control 1) Negative Feedback 2) Positive Feedback Hormone Metabolism B. Neural Control - visual/ olfactory/ gustatory C. Chronotropic Control - sleep-wake cycle/ physiologic cycle

10. Forms of Hormone in the Circulation Hormone Metabolism A. Free Molecules (unbound) - water-soluble hormones B. Bound Molecules - water insoluble hormones - bound with specific globulins or transport proteins such as albumin, “cortisol-binding globulin”, and “thyroid-binding globulin”

12. Classification of Hormones I. According to Structure A. Protein hormones 1) Simple or polypeptide [insulin, glucagon, somatostatin, growth h., ACTH, MSH, PRL, CS …] 2) Complex or glycoprotein [TSH, FSH, LH, hCG…] B. Steroid hormones [glucocorticoids, mineralocorticoids, sex androgens, retinoic a., calcitriol…] C. Biogenic amine hormones [ thyroxine,catecholamines] II. According to Mechanism of Action A. Group 1 B. Group 2 Hormone Metabolism

13. Hormone Metabolism Classification of Hormones … [Protein] A-Chain B-Chain Insulin and C-peptide Formation Ribosome ER Golgi A. Vesicles

14. Hormone Metabolism Classification of Hormones … [Protein] Pro-opiomelanocortin Peptide Family

15. Hormone Metabolism Classification of Hormones … [Steroids]

16. Classification of Hormones … [Amines] Hormone Metabolism Some Biogenic Amines Dopamine CH 2 - CH 2 – NH 2 HO HO CH - CH 2 – NHCH 3 OH HO HO Epinephrine Tetraiodothyronine Norepinephrine CH - CH 2 – NH 2 OH HO HO

17. Classification of Hormones Hormone Metabolism According to Mechanism of Action Group 1 Group 2 Type Steroids, thyroid h., Polypeptides and retinoic acid …. catecholamines… Solubility Lipophilic Hydrophilic Transport Protein Yes No Plasma T1/2 Longer Shorter Receptor Intracellular Plasma membrane Mediator HRC/HRE 2nd messengers

20. Hormone Metabolism Classes: A. Cell surface receptors B. Intracellular receptors 1) Nuclear receptors 2) Cytoplasmic receptors Receptors

21. Cell Membrane Receptors Functional Domains: 1) Ligand-binding domain 2) Transmembrane domain 3) Cytoplasmic domain Hormone Metabolism Receptors N C Typical cell membrane receptor (seven membrane-spanning domain) Extracellular Intracellular

22. Intracellular Receptors Functional Domains: 1) A hormone binding region in the C-terminal 2) An adjacent DNA binding region 3) A specifier region (N-terminal) necessary for high-affinity binding to the proper region of DNA 4) One or more regions that activate or repress gene transcription Hormone Metabolism Receptors (1) (2) (3) N C

24. Hormone Metabolism Signal Transduction Peptides Catecholamines Neurotransmitters… Steroids Thyroid hormones Estrogen, RA… Insulin, EGF, IGF-1 Growth hormone Prolactin… Signal Transduction Pathways Enzyme Activation Nucleus

25. Hormone Metabolism Mechanism of Action… [Group 1]  Cytoplasm Nucleus Hormone Action with intracellular receptors +  “ Activation”  + Specific Protein Transcription mRNA Translation mRNA Metabolic response Hormone response element (HRE) Hormone receptor complex (HRC) Receptor Steroid/Thyroid h.  Thyroid h.

26. Hormone Metabolism Mechanism of Action… [Group 1] Structural requirements for hormonal regulation of gene transcription 5’ 3’ Hormone response elements (HRE) Promoter element (PE) Gene Transcription Initiation site Termination Site 1 + Regulatory DNA region Structural DNA region

30. Mechanism of Action… [Group 2]

31. Mechanism of Action… [Coupling w/ G-protein]

32. Mechanism of Action… [Coupling w/ G-protein]

33. Mechanism of Action… [Coupling w/ G-protein]

34. Hormone Metabolism Mechanism of Action… [Group 2] Adenylate cyclase – cAMP ES Regulation through cAMP-dependent protein kinases Adenylate cyclase ATP  Mg 2+ cAMP ( • ) 5’-AMP Phosphodiesterase 4 cAMP C R R C Inactive protein kinase R R • • • • C Active protein kinase 2 + Protein Phosphoproteins Phosphatase Physiologic effects

36. Hormone Metabolism Mechanism of Action… [Group 2] Hormone Action using cAMP Second Messenger Glycogen synthase a Glycogen synthase b Protein kinase (Inactive) Protein kinase (Active) Phosphoprotein phosphatase Insulin (+) (+) (+) (+) Glycogen Phosphorylase b Glycogen Phosphorylase a Glycogen Glucose-1-PO4 (+) GLYCOGENOLYSIS Phosphorylase kinase (inactive) Phosphorylase kinase (active) Phospho- protein phosphatase Adenylate cyclase ATP cAMP (+) (-) (+) Muscles Liver

37. Hormone Metabolism Mechanism of Action… [Group 2] Hormone Action using cAMP Second Messenger Specific Protein  or  Transcription mRNA Translation mRNA Metabolic response cAMP response element (CRE) Adenylate cyclase ATP cAMP Protein kinase (Inactive) Protein kinase (Active) CREB CREB-P (+) (-) (+) Muscles Liver

38. Hormone Metabolism Mechanism of Action… [Group 2] Phosphatidylinositol Cycle and Calcium Receptor DAG IP 3 Ca ++ Protein kinase C Phosphoproteins Proteins Physiologic responses Ca ++ -Calmodulin Calmodulin kinases (+) (+) GDP GTP Phospholipase C GTP GDP (+) PIP 2 Hormone Action using DAG, IP 3 and Ca ++ as Second Messengers

39. Hormone Metabolism Mechanism of Action… [Group 2] Kinase Cascade System 1 [Autophoshorylation] (Autophosphorylation) Phosphorylation of protein substrates (Tyrosine) Cell growth DNA synthesis Early response genes Enzyme Activity Protein Translocation Gene Expression P P ES utilized by Insulin, EGF PDGF and IGF-1

40. Hormone Metabolism Mechanism of Action… [Group 2] Kinase Cascade System 2 ES utilized by Growth hormone, Prolactin, EPO, cytokines… Regulates transcription Nucleus Dimerization X = SHC GRB2 PLC  PI-3K GAP JAK P JAK P P P P P STATs X SH2 P P ) ( JAK P JAK P P P P P JAK JAK

44. Metabolic Effects of Hormones (+) Stimulated; (-) Inhibited (+) (+) (+) (+) (-) (-) (-) (-) (-) (-) (-) (+) (+) (+) “ central” “ peripheral” “ Liver” “ L & M” DM, Lepre- chaunism Glucagonoma Parkinson’s Pheochromo- cytoma Grave’s D. Myxedema Cretinism Goiter Cushing’s Conn’s Addison’s Dwarfism Gigantism Pathology Protein Synthesis Lipolysis Lipogenesis Gluconeogenesis Glycogenolysis Glycogenesis Glycolysis GH Cortisol T3, T4 Epi Glucagon Insulin Pathways (+) (-) (-) (-) (+) (+) (+) (+) (-) (-) (+) (+) (+) (+) (-) (+) (+) (+) (-) (+) (+) (-) (+) (-) (++) (+) (+) (+)

47. Hormone Metabolism Insulin … Mechanism of Action

48. Hormone Metabolism Insulin … Effects on Metabolism Enzyme Change in Activity Possible Mechanism cAMP metabolism Phosphodiesterase (low Km) Increase Phosphorylation Protein kinase (cAMP-dependent) Decrease Association of R and C subunits Glycogen metabolism Glycogen synthase Increase Dephosphorylation Phosphorylase kinase Decrease Dephosphorylation Phosphorylase Decrease Dephosphorylation Glycolysis & Gluconeogenesis Pyruvate dehydrogenase Increase Dephosphorylation Pyruvate kinase Increase Dephosphorylation Phosphofructokinase Increase Dephosphorylation Fructose-2,6-bisphosphatase Decrease Dephosphorylation

49. Hormone Metabolism Insulin … Effects on Metabolism Enzyme Change in Activity Possible Mechanism Lipid metabolism Acetyl-CoA carboxylase Increase Dephosphorylation HMG-CoA reductase Increase Dephosphorylation Triacylglycerol lipase Decrease Dephosphorylation Signaling molecules p42/44MAP kinase Increase Dephosphorylation p90RSK Increase Dephosphorylation GSK3 Decrease Dephosphorylation p70 S6 kinase Increase Dephosphorylation Phosphoprotein phosphatase Increase Dephosphorylation 1G

56. Hormone Metabolism Catecholamines … Synthesis & Structures CH 2 - C – NH 2 HO H COOH Tyrosine Dopa HO HO CH 2 - C – NH 2 H COOH Dopamine HO HO CH 2 - CH 2 – NH 2 Norepinephrine HO HO CH - CH 2 – NH 2 OH Epinephrine HO HO CH - CH 2 – NH CH 3 OH Tyrosine hydroxylase Dopa decarboxylase Dopamine  -hydroxylase PNMT

57. Catecholamines … Biosynthesis Hormone Metabolism Chromaffin Cell Tyrosine (+)  - adrtenergic & cholinergic agents (-)  -adrenergic agents E E NE NE Tyrosine Dopa Dopamine Granule E NE NE DBH TH DD PNMT

58. Hormone Metabolism Catecholamines … Secretion of Stress Hormones Stress Hypothalamus ACTH Cortisol EP Blood glucose Blood Tyr, Phe Chromaffin Cell EP EP Tyrosine NEP PNMT

64. Steroids … Hormone Metabolism Synthesis Pregnenolone Progesterone Cortisol, Aldosterone , etc. Cholesterol (1) SCC (2) Oxidation & isomerization (3) Hydroxylation

65. Steroids … Hormone Metabolism Subcellular comparmentalization of Glucocorticoid biosynthesis R ACTH G AC Cortisol Cholesterol Ester Cholesterol Lipase Pregnenolone ATP cAMP Protein kinase A Cholesterol Cortisol Progesterone 11-Deoxycortisol ER LDL

66. Steroids … Mechanism of Action

69. Steroids … Hormone Metabolism “ High level of serum cortisol may be responsible for stress-induced memory loss.” “ Physiologic response to stress does not impair the learning aspect of memory but only the free recall of information.” “ Elevated glucocorticoid level may induce impairment in such stressful conditions as job interviews, combat, courtroom testimony and examinations.” [Nature Neuro-science 2000; 3:313-4 (April)]

70. Growth H. … Secretion

71. Growth H. … Mechanism of Action

74. Pygmies

86. Hormone Metabolism PTH Actions PTH  (+) G-protein  cAMP BONES KIDNEYS INTESTINES

89. Synthesis of Calcitriol Hormone Metabolism 7-dehydrocholesterol 25-OH-D3 SKIN Vit D3 1, 25-(OH) 2 -D3 LIVER KIDNEY [placenta] (Photolysis) (25-hydroxylase) (1-hydroxylase)

91. When you do not succeed in taking giant steps on the road to your goal, be satisfied with little steps, and wait patiently till the time that you are able to run, or better still, to fly. Be satisfied to be a little bee in the hive who will soon become a big bee capable of making honey… Thank you … (Padre Pio)